West Nile virus (WNV) is a model flavivirus and an NIAID Category B infectious/emerging agent. It is currently the leading cause of viral encephalitis in the United States and an ongoing public health threat globally. WNV can cause severe and fatal neurological diseases. There are no vaccines or antiviral therapeutics to prevent or treat WNV infection. Therefore, there is an imminent need to understand the immunological processes by which the virus is controlled in order to facilitate therapeutic strategies against infection. IRF5 is a key transcription factor for the induction of immune-modulating cytokines. Our recent studies indicate that virus signaling of IRF5 activation and the induction and function of IRF5-target genes in dendritic cells (DCs) are essential components of antiviral immunity. However, a major void exists in the understanding of IRF5 activation and function, as signaling pathways and mechanisms of IRF5 activation, IRF5 transcriptional targets, and overall function of IRF5 in programming DC effector actions are not known. Studies in this proposal focus on defining the regulation and functions of IRF5 in DCs for the control of WNV infection. This proposal aims to test the hypothesis that IRF5 is essential for type I interferon and cytokine production in DCs for the effective control of WNV infection. Specifically, we will (1) define the signaling pathways and mechanisms of activation of IRF5, and (2) characterize the IRF5 target genes for antiviral actions. Together, these studies will advance our knowledge in IRF5 activation upon virus sensing in the host, and the effector function of IRF5 target genes in programming effective immune response against virus infection. Insights can lead to development of therapeutic and preventative action against flavivirus disease.